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Obfuscation On Human / Swine H3N2v Sub-Clades
Recombinomics
Commentary 15:45
August 20, 2012
The good news is that the main risk factor for H3N2v virus infection continues to be exposure to pigs.
The above comments from the August 17 CDC update, which again cites USDA data to support the CDC position that the H3N2v cases at agricultural fairs is due to transmission to humans from infected swine at the fairs. However, the CDC has released full sequences from the H3N2v cases and the USDA has been releasing sequences from swine, including H3N2v matches, which have significant discordance and do not support frequent transmission of H3N2v from swine to humans. The continue obfuscation by the CDC on the sub-clade differences between the first 10 H3N2v human cases in 2011 and all of the 2012 human cases continues to create severe bias is sample collection and testing which strengthens the artificial link between H3N2v cases and swine exposure.
The CDC sequences from patients shows clear human adaption of H3N2v, which includes significant changes that appear in human cases prior to appearance in swine, supporting common transmission from human to swine.
The first human H3N2v was in the summer of 2009 and the sequences had internal genes related to an H1N1v outbreak at the 2007 Huron County Fair, which involved two confirmed cases, a presenter and her father (A/Ohio/01/2007 and A/Ohio/02/2007). Moreover, 26 attendees of the fair had ILI (influenza-like illness), signaling extensive transmission to humans.
The first H3N2v case, A/Kansas/13/2009 from a 7/27/2009 isolate,, had a modification of the PB1 gene, E618D, which was not in the Huron County sequences or swine sequences, other than those infected with H1N1pdm09, which had E618D (in human infections of other species, including swine). The first swine triple reassortant sequence with E618D was in the fall of 2010, more than a year after the first human cases. In 2010, all human H3N2v sequences had PB1 E618D, including the first 2010 case, A/Minnesota/09/2010, which was from a 5/27/2010 isolate.
In 2011 the human H3N2v sequences demonstrated reassortment between the dominant sequence in the 2010 human cases and widely circulating H1N2. A full sequence from an Ohio swine isolate, had a match with the PB1, NA, and MP gene of the first human H3N2v case, A/ Indiana/08/2010, while remaining five gene segments (PB2, PA, HA, PA,NS) match the dominant 2010 human H3N2v sequences. The H1N2 MP gene had been acquired from H1N1pdm09, which had been shown to be associated with adaptation to airborne transmission I a guinea pig model.
The initial Indiana case had no swine exposure, but his caretaker, who was asymptomatic, had exhibited swine, which were also asymptomatic. Consequently, the CDC cited “indirect” swine exposure, even though neither the contact nor the swine were symptomatic.
The next nine confirmed human cases had the same constellation of genes, further supportinghuman adaptation and transmission. The most recent cases with this constellation was found in three epidemiologically linked cases in Iowa (A/Iowa/07/2011, A/Iowa/08/2011, A/Iowa/09/2011) and the father and brother of the index case were symptomatic. However, none of the Iowa cases had swine contact exposure or contact, signaling human to human transmission.
However, the final two confirmed cases in 2011 were from a Mineral County day care center in West Virginia (A/West Virginia/06/2011 and A/West Virginia/07/2011), were the was also no swine contact or exposure, had a novel constellation where the NA gene, which was linked to a swine H1N2 lineage, was replaced with an NA gene which had a swine H3N2 lineage. The acquisition of this gene via reassortment defines a series of differences between the two lineages which allows for easy and convincing distinctions.
The cluster in West Virginia drew considerable attention because the two cases were infected two weeks apart, signaling extensive human to human transmission. An initial epidemiological analysis identified IL in 23 of the 70 contacts of the index case, signaling extensive and sustained human to human transmission. This outbreak led to two MMWRs (end of 2011 and beginning of 2012), as well as a series of CDC documents with new H3N2v guidelines as well as a fifty state conference call.
However, this added attention failed to identify any H3N2v cases during the peak of the 2011/2012 flu season. The first H3N2v case in 2012 was from a March 27, 2012 collection in Utah, A/Utah/10/2012, and it matched the novel sub-clade identified in the West Virginia clusters.
The Utah case was followed by a large series of collections from July, 2012 collections. The first case was from Maui, Hawaii, A/Hawaii/03/2012, and was followed by six sets of sequences from outbreaks in Indiana and Ohio. Four identical sequences were from the LaPorte County Fair (A/Indiana/06/2012, A/Indiana/07/2012, A/Indiana/08/2012, A/Indiana/09/2012), while additional sequences were from Jackson County (A/Indiana/12/2012), and the Butler County fair in Ohio (A/Ohio/13/2012).
This initial series was followed by 10 additional sets of sequences. Six were from Ohio (A/Ohio/14/2012, A/Ohio/15/ 2012, A/Ohio/16/ 2012, A/Ohio/17/2012, A/Ohio/18/ 2012, A/Ohio/20/ 2012) and were closely related to the initial Butler County Fair sequence. Two of the four Indiana sequences, A/Indiana/13/2012 and A/Indiana/17/2012, were relate to but distinct from the Jackson County sequences, while the other two sequences from Indiana, A/Indiana/15/2012 and A/Indiana/19/2012, which are closely related to each other, but distinct from the other July H3N2v sequences.
All of the 17 July isolates matched the West Virginia sub-clade, again signaling human adaptation and evolution away from swine sequences.
The USDA has enhanced swine surveillance following the 2009 pandemic. The vast majority of the USDA swine sequences include full sequences from NA, NA. and MP. Therefore matches with the two novel sub-clade, based on these three gene segments is straight-forward. A recent publication on the emergence of the sub-clade found in the initial human sub-clade in 2011 looked at 388 sets of sequences with a minimum of HA/NA/MP sequences isolated from swine in 2009-2011.. Although this analysis noted the increasing presence of the H1N1pdm09 M gene, there was significant diversity in serotypes and constellations, and only one match was identified which was the New York isolate (A/swine/NY/A01104005/2011) noted previously, which was collected after the initial human cases.
The USDA released sequences from more recent collections, and six additional matches were identified from four swine cases in Iowa and Illinois, but all collections were after the New York isolate. More recently released sequences increased the number of swine matches to 28, including three isolates from samples collected prior to the New York sequence, (A/swine/Iowa/A01202529/2011 and A/swine/Iowa/A01202530/2011, were collected on August 22, 2011, while A/swine/Iowa/A01202573/2011 was collected September 07, 2011 but after the initial human cases in July. Moreover, the matches included four Ohio isolates from June, 2012 samples (A/swine/Ohio/1/2012, A/swine/Ohio/6/2012, A/swine/Ohio/7/2012, A/swine/Ohio/9/2012,). Thus, none of the samples were collected prior to the first human case in 2011.
However, only two of the isolates matched the novel sub-clade seen in the West Virginia cluster as well as all 2012 human cases. Both of these isolates were from 2012, and therefore after the initial human cases in 2011.
The detection of the novel sub-clade in only 2 of 26 swine isolates which matched the human cases in 2011 and 2012 raised significant doubt about the role of swine in the appearance and explosion of human cases in the West Virginia cluster and the 2012 human cases.
Moreover, the absence of any human cases in 2012 which match the sub-clade seen in initial human cases in 2011, in spite of detection of this sub-clade in 12/14 swine isolates from 2012, greatly diminishes the role of swine in the 2012 infections.
Instead the linkage to agricultural fairs is linked to the targeting of ILI cases with swine exposure, which creates the artificial link. Although the CDC has recently announced expansion of testing of ILI cases without swine linkage, the intense focus on the linkage to swine exposure at fairs continues to heavily bias testing of these cases, which is facilitated by the CDC obfuscation on the two sub-clades and the failure of the CDC to acknowledge the clade distinction between all of the 2012 H3N2v cases and the initial 10 cases in 2011.
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